In this proposal, I outline a research program that may offer a unifying adaptive root for patterns of codon bias. The choice of preferred codons will be examined to determine whether this choice was shaped, as was the code, by the need to minimize the physico-chemical change resulting from translational errors. Further, codon preferences at sites or in domains of known function will be examined to determine whether the functionality directs the physico-chemical property for which error- minimization is most extreme. In addition, codon preferences in bacteriophage and viral genomes will be examined with respect to the biological roles of viral proteins and protein domains to determine whether codon preferences can mediate mutational variability. While various sequence motifs have been shown to increase mutational variability by increasing the local mutation rate, codon preferences could moderate the degree of mutational variability by altering the effect of mutations instead. Using comparisons of amino acid differences among natural isolates and the results of previously conducted laboratory evolution experiments as guides, codon preferences will be examined to see if high-error codons are used at sites important for adaptation to novel hosts/environments or for evasion of host immune responses. The integration of sequence analyses with observations of adaptive variation among natural and laboratory populations will help address fundamental questions about the evolution of pathogens.